LIPOXYGENATION OF ARACHIDONIC ACID: A PIVOTAL STEP IN STIMULUS-SECRETION COUPLING IN THE PANCREATIC BETA CELL

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Abstract
The relationship(s) between calcium flux, phospholipid turnover and stimulus-secretion coupling in endocrine cells remains unclear. Several stimuli of insulin secretion promote calcium accumulation in the pancreatic beta cell; recent studies are compatible with the formulation that, as a consequence of such ion flux, arachidonic acid is released from phospholipids by calcium-dependent phospholipase(s), and may, in turn, be metabolized via lipoxygenase to products which promote insulin releage. In the current study, we examined the effects of two known lipoxygenase inhibitors, BW755c and nordihydroguaiaretic acid, on the augmentation of insulin release evoked by three pharmacologically distinct classes of insulin secretagogues–one which augments cyclic AMP accumulation (exemplified by theophylline), one which inhibits prostaglandin synthesis (sodium salicylate), and one which is independent of changes in cyclic AMP or prostaglandin availability (tolbutamide). Both inhibitors of lipoxygenase markedly blunted the insulinogenic response to glucose,as well as to all three drugs, without evidence of cell toxicity. These data are most compatible with a central role for lipoxygenase products in coupling insulin secretion to stimuli of widely varying natures.